Thyroid hormone is an important regulator of vertebrate development and homeostasis. Yen, Physiol. Rev. 81: 1097-1142, 2001. Thyroid hormone is critical for normal fetal brain development, and brain disorders such as cretinism can result from a lack of thyroid hormone in the developing fetus. In adults, thyroid hormone exerts effects in almost all tissues, and important processes such as metabolic rate, thermal regulation, lipid inventory, cardiac function, and bone maintenance are affected by thyroid hormone. Individuals with excess blood levels of thyroid hormone (hyperthyroid) generally have elevated metabolic rate and body temperature, decreased serum cholesterol, and increased heart rate compared to those with normal thyroid hormone levels (euthyroid). Conversely, hypothyroidism is characterized by depressed metabolic rate and body temperature, elevated serum cholesterol, and decreased heart rate compared to euthyroid controls.
Thyroxine (T4, FIG. 1) is the predominant form of thyroid hormone that is secreted from the thyroid gland, and T4 is converted to the more physiologically active 3,5,3′-triiodothyronine (T3, FIG. 1) by enzymatic deiodination in peripheral target tissues. Three different deiodinases have been identified to date (D-I, D-II, and D-III). The D-1 and D-II enzymes mediate “outer ring” deiodination such as the conversion of T4 to T3, whereas the D-III enzyme mediates “inner ring” deiodination, exemplified by the conversion of T4 to reverse-T3 (rT3, FIG. 1). To date, no significant biological activity has been ascribed to rT3 even though significant blood levels of this metabolite are found. Moreover, a variety of further deiodinated forms of T4 are known to exist in vivo and the biological significance of these metabolites in unclear.
The majority of known biological activities of thyroid hormone are mediated by binding of T3 to thyroid hormone receptors (TRs). The TRs belong to the nuclear receptor superfamily of hormone-activated transcription factors, and there are two different TR genes, TRα and TRβ. The mRNAs of TRα and TRβ are further processed giving rise to four TR isoforms (TRα1, TRα2, TRβ1, TRβ2) that are co-expressed in ratios that are unique to each tissue. T3 binds to the ligand binding domain (LBD) of nuclear localized TRs, and the activated TR regulates the transcription of hormone responsive genes. In this mode of action, the effects of thyroid hormone are manifested exclusively through positive and negative regulation of hormone-responsive gene transcription.
There are, however, physiological effects of thyroid hormone that are not readily explained by a transcription regulation mode of action. These so-called “non-genomic effects” are characterized by a rapid onset in response to hormone and/or insensitivity to translation inhibitors, such as cyclohexamide. Specific examples of such effects include the rapid contractile response to T3 in cultured cardiac myocytes, the shortening of the action potential with concomitant attenuation of repolarizing currents in ventricular myocytes, and in studies in animals. Falkenstein, et al., Pharmacol. Rev. 52: 513-555, 2000; Walker, et al., J. Thorac. Cardiovasc. Surg. 108: 672-679, 1994; Sun, et al., Am. J. Physiol. Endocrinol. Metab. 278: E302-E307, 2000; Hamilton, et al., Am. J. Cardiol. 81: 443-447, 1998; Buu-Hoi, et al., Pharmacology 2: 281-287, 1969; Boissier, et al., Eur. J. Pharmacol. 22: 141-149, 1973; Cote, et al., Cardiovascular Res. 8: 721-730, 1974. The rapid rate of these effects suggests that they are mediated by receptors other than the nuclear TRs in response to a thyroid hormone. The source and mechanism of these non-genomic effects are not known. Dratman, J theor. Biol., 46: 255-270, 1974; Han, et al., Int. J. Peptide Protein Res. 30: 652-661 1987; Rozanov et al., Neuroscience, 74: 897-915, 1996; Tomita et al., J. Biol. Chem. 219: 595-604, 1956. A need exists in the art to understand and regulate/modulate these non-genomic effects related to thyroid hormone. The present invention is directed to these, as well as other important ends.